Stent with collagen

ABSTRACT

A method of depositing collagen coatings on a metal surface, namely metal stents, by electrodeposition.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 08/429,308,filed on Apr. 26, 1995, now U.S. Pat. No. 5,693,085, which is acontinuation-in-part of application Ser. No. 08/350,223, filed on Dec.6, 1994, now abandoned, which is a continuation-in-part of applicationSer. No. 08/235,300, filed on Apr. 29, 1994, now abandoned, thedisclosures of which are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

This invention relates to vascular prostheses of improvedbiocompatability and more specifically to stents in combination with acollagen material. Such a combination provides an endovascular stentwhich protects the vascular wall and forms a non-thrombogenic cushionfor the stent in the vascular lumen.

It also relates to stents in combination with a collagen liner material.Such a combination provides an endoluminal stent which engages theluminal wall and in the case of vascular applications, forms anon-thrombogenic surface as well as providing for the growth ofendothelial cells, as well as a reservoir or point of attachment fortherapeutic agents in any application.

It also relates to combinations of both of the foregoing arrangements.

Broadly, it relates to stents associated with an outer covering ofcollagen material and/or a luminal liner of same. It also relates to amethod of applying collagen to the interior of a vessel or the like as aliner by using a stent.

Stents are generally tubular in configuration, are open ended, and areradially expandable between a generally unexpanded insertion diameterand an expanded implantation diameter which is greater than theunexpanded insertion diameter. Such intravascular implants are used formaintaining vascular patency in humans and animals.

Stents are typically placed or implanted by a mechanical transluminalprocedure. One common procedure for implanting a stent is to first openthe region of the vessels with a balloon catheter and then place thestent in a position that bridges the treated portion of the vessel bymeans of a placement catheter.

Prior art patents refer to the construction and design of stents as wellas apparatus for positioning stents within a vessel. In general, forexample, such patents disclose a technique for positioning an elongatedcylindrical stent at a region of an aneurysm, stenosis or the like. Thestent expands as necessary to an implanted configuration after insertionwith the aid of a catheter.

Specifically, U.S. Pat. No. 4,733,665 to Palmaz which issued Mar. 29,1988, discloses a number of stent configurations for implantation withthe aid of a catheter. The catheter includes means for mounting andretaining the stent, preferably on an inflatable portion of thecatheter. The stent is implanted by positioning it within the bloodvessel and monitoring its position on a viewing monitor. Once the stentis properly positioned, the catheter is expanded and the stent separatedfrom the catheter body. The catheter can then be withdrawn from thesubject, leaving the stent in place within the blood vessel. U.S. Pat.No. 4,950,227 to Savin et al., which issued on Aug. 21, 1990 is similar.

Another similar U.S. Pat. No. 5,019,090 discloses a generallycylindrical stent and a technique for implanting it using a deflatedballoon catheter to position the stent within a vessel. Once the stentis properly positioned the balloon is inflated to press the stentagainst the inner wall linings of the vessel. The balloon is thendeflated and withdrawn from the vessel, leaving the stent in place.

A patent to Dotter, U.S. Pat. No. 4,503,569 which issued Mar. 12, 1985discloses a spring stent which expands to an implanted configurationwith a change in temperature. The spring stent is implanted in a coiledorientation and heated to cause the spring to expand due to thecharacteristics of the shape memory alloy from which the stent is made.Similarly, U.S. Pat. No. 4,512,338 to Balko et al., which issued Apr.23, 1985, discloses a shape memory alloy stent and method for itsdelivery and use other kinds of self-expanding stents are known in theart.

The delivery and expansion of the stent of the invention is the same asthat already known in the art and practiced with the stent of FIGS. 1and 6. U.S. Pat. No. 5,195,984 to Schatz, issued Mar. 23, 1993,describes a typical balloon expansion procedure for an expandable stent.This patent is incorporated in its entirety herein by reference. Thatpatent describes a catheter having an expandable inflatable portionassociated therewith. In a conventional manner, the catheter and stentare delivered to a desired location within a body passageway at which itis desired to expand the stent for implantation. Fluoroscopy, and orother conventional techniques may be utilized to insure that thecatheter and graft are delivered to the desired location. The stent isthen controllably expanded and deformed by controllably expanding theexpandable inflatable portion of catheter, typically a balloon. As aresult the stent is deformed radially outwardly into contact with thewalls of the body passageway. In this regard, the expandable inflatableportion of the catheter may be a conventional angioplasty balloon as isalready known in the art. After the desired expansion and deformation ofthe stent has been accomplished, the angioplasty balloon may be deflatedand the catheter removed in a conventional manner from the passageway.

Also, this invention is useful in self-expanding stents such as thosedisclosed in U.S. Pat. Nos. 4,732,152 and 4,848,343, both of which areincorporated herein by reference.

All of the above-identified patents are incorporated herein byreference.

SUMMARY OF THE INVENTION

In one preferred form a metal or other stent is delivered for vascularimplantation with a covering sleeve of collagen material. If the stentis of the variable diameter type, the sleeve may be stretched into placeor otherwise positioned between the stent and the vascular wall when thestent is seated or deployed. A drug or other agent such as heparin orthe like may be included in the collagen for release after stentdeployment.

In another preferred form a metal or other stent is delivered forvascular implantation with a luminal liner of collagen material. A drugor other agent such as heparin or the like may be included in thecollagen as a surface treatment or for release after stent deployment.

In yet another preferred form, a stent is provided with both an innercollagen liner and outer collagen coating.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a stent and covering sleeve combination being formedaccording to the invention.

FIG. 2 is a fragmentary showing of collagen with a fabric support.

FIG. 3 shows an example of another self-expanding stent configurationuseful in the invention.

FIG. 4 shows another stent configuration useful in the invention.

FIGS. 5 and 6 show a flexible stent configuration which may incorporatea covering sleeve according to the invention.

FIG. 7 is similar to FIG. 1, showing a combination being formedincluding an internal liner and an external sleeve for a stent,according to the invention.

FIG. 8 is a showing of an alternate mode of manufacture of the inventionby molding the collagen to the stent.

FIG. 9 shows a stent and an internal liner sleeve combination beingformed according to the invention.

FIGS. 10 shows a bilayer collagen material in schematic and fragmentaryform.

FIGS. 11, 12, and 13 are schematic longitudinal cross-sectional views ofa stent carrying inner and outer layers of collagen material.

FIG. 14 is a showing of an alternate stent/liner arrangement.

FIG. 15 shows an optional technique for forming the stent/linerarrangement by molding.

FIGS. 16, 17, and 18, schematically show the stretch of a collagen stentbeing oriented on a bias with respect to a stent.

FIGS. 19 and 20 show a coated stent, FIG. 20 being a cross-sectionalview of FIG. 19.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring now to FIG. 1, a tubular metal stent generally indicated at 10is shown being combined with a covering sleeve of collagen materialgenerally indicated at 12 to provide the combination stent/sleevegenerally indicated at 14 for the purpose of vascular implantation.

Stent 10 is of the type, typically of a metal such as for examplestainless steel, nitinol, superelastic alloys and other metals or asuitable polymeric plastic and may be of a fixed diameter or of avariable diameter, the latter being more preferred and well known in theart. The variable diameter type are usually either balloon expandable orself-expanding, both of which are also known in the art. Examples of theformer type are shown in U.S. Pat. No. 4,733,665, U.S. Pat. No.4,739,762 and U.S. Pat. No. 4,776,337, all of which are incorporatedherein by reference. The latter type is preferred for the purposes ofthis invention at present, i.e., self-expanding, particularly those madeof Nitinol an example of which is discussed in the U.S. Pat. Nos.4,503,569 and 4,512,338, also incorporated herein by reference. Also,for example, useful stents are shown in co-pending application Ser. No.08/246,320 filed May 19, 1994 entitled “Improved Tissue SupportingDevices”. The content of this application is incorporated herein byreference.

In any event, generally a stent provides a supporting frameworkstructure which may take many forms. Typically stents are open orperforate and may be comprised of a network of struts or wire-likestructure. Stent 10 is comprised of struts.

Collagen sleeve 12 shown in FIG. 1 may be comprised of collagen per seor it 12 a may be carried on a support 12 b as shown in FIG. 2, support12 b being of DACRON® fabric or the like as is known and disclosed forexample in U.S. Pat. Nos. 5,256,418, 5,201,764 and 5,197,977, the entirecontent of which are all incorporated herein by reference, particularlythose portions which relate to the formation of collagen tubes. TheSupport 12 b may be a fabric, woven or braided, and may also be ofpolyester, polyethylene, polyurethane or PTFE. The term “collagenmaterial” is used herein to refer to both supported and unsupportedcollagen for the sleeve element of this invention.

The preferred collagen at present appears, for the purposes of thisinvention, to be that composed of bovine or porcine Type I or Type IVcollagen and combinations thereof in bilayer sheet-like form. Thecollagen may also be made of Type III or combinations of any of thevarious types. U.S. Pat. Nos. 4,837,379; 4,902,508; 4,950,483;4,956,178; 5,106,949; 5,110,604, 5,256,418; 5,275,826; 5,281,422 and5,024,841 relate to collagen compositions and production useful in thisinvention and are incorporated herein by reference. Collagen can beextracted from various structural tissues as is known in the art andreformed into sheets or tubes and dried onto a stent. Generally, thethickness of these sheets or tubes will range from about 5 to 200microns. One preferred collagen at present is that disclosed in U.S.Pat. No. 4,902,508 coated as described in U.S. Pat. No. 5,275,826 toprovide bilayer SIS as described further hereinbelow. Another preferredcollagen is that described as a “collagen construct” in U.S. Pat. No.5,256,418, particularly in which the permeable substrate is alsocollagen.

Cells of the blood vessel wall synthesize and secrete several kinds ofmacromolecules forming extracellular matrix. The components of thismatrix comprise several large proteins that may be syntheticallyconstructed to form films, tubes or multilayer sheets or otherconstructs. Among these biological components are collagens of severaltypes, elastin, glycosaminoglycans (GAGS), fibronectin and laminin.Collagens are three chain glycoproteins with molecular weights of about300,000. Elastin is an insoluble nonpolar amine acid rich crosslinkedprotein. The GAGs are linear chain polysaccharides with various negativecharges with various molecular weights ranging from thousands tomillions. Included in the GAGs are heparin and heparin sulfate, dermatinsulfate and chondroitin sulfate. Fibronectin is a 440,000 MW 2-chainadhesive glycoprotein that acts as a substrate for many cell types andin cell-cell interactions. Laminin is a 2 chain glycoprotein of MW about850,000 and acts as a basement membrane structure for cellular-molecularinteractions. Each of these macromolecules may be combined in amultitude of combinations to form composites. These are all naturalmaterials that serve specific functions and are exposed to blood undernormal repair conditions. It is therefore expected that, if a coveringsleeve for a stent were made of these macromolecules and used in thecourse of intervention, repair of a blood vessel would proceed morenaturally than if a similar device were constructed of syntheticpolymers such as polyethylene, polyteraphthalate or polyurethanes. Suchmaterials are also referred to herein generally as “collagen”. The term“collagen” herein thus refers to not only the specific class ofmacromolecules known as collagen but those natural materials thatnormally or naturally form membranes with collagen such as laminin,keratin, glycosaminoglycans, proteoglycans, pure carbohydrates, fibrin,fibronectin, hyaluronic acid or the like, and other natural materialsthat come into contact with collagen that can be made into film,including albumin, globulins, and other blood borne proteins. Tubularfilms made from any combination of the above materials will providesubstantially the same purpose as that of pure collagen.

The interaction of blood with the differing membrane componentsdescribed above determines subsequent reactions in the repair of bloodvaseulature. The initial thrombus formation adhesion and activation ofplatelets and the initial events related to intimal hyperplasia such asdamage to the internal elastic lamina are among those events. Theseevents are natural components of the repair process. Normally theseevents do not hamper the flow conditions of blood except in the cases ofsevere trauma. Microthrombi constantly form and disperse on blood vesselsurfaces so it would be advantageous to form stent or graft coverings ofmaterials that are accustomed to having thrombus form so that subsequentlysis reactions of those thrombi can proceed in a natural andunobtrusive manner. A sleeve or liner made of these macromolecularcomponents forming a protective layer will prove advantageous when usedwith stents. Metal or polymeric stents which will provide mechanicalstability to the arterial wall to hold up dissected tissue may also beused to hold a sleeve comprised of collagen.

Nevertheless, because anything not formed in the body as a naturalcomponent may elicit extreme and unexpected responses as blood vesselclosure due to thrombus formation or spasm and because damage to bloodvessels by the act of insertion itself of a device may be extreme andunduly injurious to the blood vessel surface, it is prudent to protectagainst such events. The materials described above are capable of beingmanipulated to become hydrophilic or hydrophobic with thicknessesranging from about 5 to several hundred microns. They can be made watersoluble, insoluble and with various porosities. They can also beconstructed to have regions of various hydrophilicity and porosity.Porosity control is well known.

As such, stent sleeves or liners constructed of these materials can beused for reservoirs for pharmaceutical agents and the like. Hydrophilicdrugs such as heparin or hirudin to protect against coagulation orhydrophobic drugs such as prostaglandins or aspirin and vitamin E may beused to protect against platelet activation. Vitamin E and other antioxidants such as sodium ascorbate, phendies, carbazoles, andtocotrienols may be used to protect against oxidation. Most preferably,the collagen material will include a quantity of drug material such asheparin which may be incorporated into the collagen in known manner forrelease after placement of the stent. Generally, the drug materials mayinclude the known antitirombic agents, antibacterial and/orantimicrobial agents, antifungal agents and the like.

During the formation process of the sleeve or sheet, various componentsmay be added to the solution prior to drying or may be added separatelyafter formation of the device. Heparin may be directly added to theforming solution as may be aspirin. Benzalkonium heparin, a modifiedform of heparin which makes it more hydrophobic may be used to coat theformed device or film from a solution of alcohol. Prostaglandins PGI2 orPGE2 may be added from a solution of propanol or propanol/methylenechloride onto a collagen sleeve formed from an aqueous base. Vitamin Emay be added from even less polar solutions as chloroform. RGD peptide,thrombolmiodulin, TPA (Tissue Plasminogen Activator) and Urokinase areexamples of bioactive proteins which may be added. Gene therapy agentssuch as antiplatelet and antibody fragments, for example GB2B3A may beincluded. Other agents could be similarly added. The term “agents” isused herein to include all such additives.

Vitamin E is a known antioxidant. It is used in polymers and as a drug.It could also be used in biodegradable stents for multiple purposes. Inthose polymeric type stents that require some form of energy as heat orlight to be delivered it could serve to protect the polymers thereinagainst unwanted oxidation caused by the energy source. Also, becausetissue damage is caused by oxidation originating from cellularcomponents as macrophages and neutrophils, Vitamin E could serve toprotect the tissue as it leached from implanted devices. It could alsoserve to protect the polymer during extrusion or heat forming aspressing films. It could also serve to plasticize the material in placeof using other non FDA approved materials. It is therefore contemplatedthat Vitamin E may also be used in combination with the stent orcollagen material or the like in this invention for several purposes.

A primary result of the use of a collagen sleeve made of naturalcomponents is that cellular regrowth of endothelium will take place ontoa natural substrate that is essentially undamaged and uniform andprotects against tissue flaps and exposure of necrotic orarthrosclerotic tissue to blood. In this regard, the sleeve providesbiological protection.

Metal stents are known to sometimes physically damage tissue uponexpansion. A sleeve made of a biological material is naturally soft bycomparison to the metals or polymers used to construct stents. A sleevecomprised of collagen may be made sufficiently thick and durable so thatit will prevent or at a minimum reduce any damage caused by the strutsor other elements of any of the metal stents to the remaining healthyendothelium and the internal elastic lamina. The porosity of the sleevemay permit diffusion of essential fluid components from the blood to thesurviving tissue below. In this regard, the benefit of the biologicaltissue protection by the sleeve and the physical protection provided areadditive.

Both the biological and physical advantages as described herein can notbe provided by synthetic sleeves as Dacron or PTFE.

In the case of a fixed diameter stent, the sleeve may be fitted to thestent rather closely for ease of vascular placement. However, in thecase of variable diameter stents, the sleeve being somewhat elastic willfit the constricted stent and stretch with it upon deployment or it maybe relatively loose fitting to accommodate the expanded stent upondeployment without any additional stress. Alternatively and mostpreferably, the stent may be expanded temporarily and the collagenplaced thereon. The collagen may then be hydrated and the stentcontracted to its unexpanded configuration. Then the collagen isdehydrated and it fits tightly to the stent.

A sleeve or a liner may be made to be more elastic by altering thecrosslink density of the collagen. This can be accomplished in a varietyof ways.

Collagen sleeves may be prepared to have a very low crosslink density.The crosslink density may be increased in a variety of ways,dehydration, radiation exposure or heating are some examples of ways.Chemical agents which react with the collagen, such as short chaindialdehydes or formaldehyde may be employed to crosslink the collagen.The avoidance of the aforementioned processes can assure anon-crosslinked structure and result in somewhat elastic material.Crosslinking with the appropriate reagents can also enhance theelasticity of the collagen sleeve. Such reagents are the long chaindifunctional molecules C12 and higher such as polyether or aliphaticdialdehydes, activated diesters such as N-hydroxy succinimide esters anddiacid chlorides. These active esters will react with amines present onthe collagen chains thus bridging them by a flexible link which allowsexpansion without failure and tearing. Also, with amine functionalityprotected as an amide, the interchain, irreversible amide formation,which results from dehydration, is prevented.

A variety of stent types may be used in the invention. Some examples areshown in FIGS. 3-6. In FIG. 3 there is shown a braided self-expandingstent generally designated 40. As is clear from the Figure, stent 40 hasa cylindrical configuration. The stent may be manufactured in a braidingmachine, wherein the stainless steel monofilaments consist of aplurality of wires, each having a thickness of, for example, 0.08 mm.FIG. 4 shows yet another stent configuration 50 which may be used inthis invention. Other examples of this type of stent are disclosed inU.S. Pat. No. 4,655,771; U.S. Pat. No. 4,732,152; U.S. Pat. No.4,954,126 and U.S. Pat. No. 5,061,275; all of which are incorporatedherein by reference.

Referring now to FIGS. 5 and 6 an articulated stent 60 is shown withthree stent segments 62 and two interconnecting hinge elements 64. Stentsegments 62 are each made of individual wire elements welded together.Hinges 64 may be made of biocompatible spring material and may be of asmaller diameter than those used in forming stent segments 62. Hinges 64are welded at each end to stent segments 62 using either laser orresistance welding techniques. Hinges 64 are preferably both attached tothe same side of stent segments 62. Stent 60, shown in FIG. 5, may beinstalled in an artery 66 with a sleeve 12 as shown in FIG. 6 and may bebent as shown.

Other stent configurations and materials will be apparent to thosefamiliar with this art.

Collagen sleeves may be made to cover both sides of the stent, insideand out so that its surfaces are entirely encompassed by collagen.

An example of one such embodiment is shown in FIG. 7 which comprises atubular stent generally indicated at 10 combined with an inner sleeve 13of collagen material and an outer sleeve 12 of collagen material whichprovide in combination a stent/sleeve generally indicated at 15 for thepurpose of vascular implantation. In some cases, it is preferred thatthe collagen sleeve 13 be joined to the interior surface of the stent bya suitable means such as collagen gel which acts as an adhesive,particularly when the stent is of the variable diameter type. Such gelsare known in the art.

EXAMPLE

Method for the preparation of the sleeve stent of FIG. 7.

1. SIS sheet is stretched about 50% while allowed to air dry.

2. Dry SIS sheet is wrapped onto an inflated, standard angioplastyballoon, moistening along the seam to ensure proper adhesion.

3. A tubular stent is then placed over the SIS.

4. A second sheet of SIS is wrapped over the exterior of the stent. Thissheet may be wetted to facilitate handling. The SIS which resides insidethe stent may be wetted with a small amount of distilled waterimmediately preceding this wrapping procedure also.

5. Open cell foam sheeting is then wrapped onto the outer second layerof collagen, followed by a wrap of dialysis tubing. This radial pressureinsures continuous contact and adhesion between the collagen layers.

6. The entire construction is then immersed in water momentarily to wetthe collagen.

7. The entire combination is then heated to about 40°-70° C. for about0.5 -3 hours, then cooled to room temperature. The purpose of this heattreatment is to bond the collagen layers together. It may optionally beaccomplished by use of a chemical cross-linking agent.

8. The resultant device is liberated from the balloon after the dialysistubing and foam are removed. Any excess collagen material is thentrimmed from the ends of the covered stent.

A cast or molded version is shown being manufactured in FIG. 8 whichincludes a cylindrical mold 80 into which a cylindrical stent 82 isplaced on end. Preferably, mold 80 will be porous, such as a porousceramic, so as to allow water to be drawn through the mold to facilitateset-up of the poured collagen. A collagen gel solution 83 is then pouredinto mold 80 around stent 82 and inside of stent 82 and allowed toset-up. Upon set-up, the stent embedded in collagen is removed from themold and a longitudinal hole may be formed through the collagen insidethe stent to provide a longitudinal opening therethrough. Otherwise, amandrel or mold insert may be used for this purpose as well.

In other embodiments, the collagen material may be coated onto the stentsurfaces as desired by spraying or dip coating or an electrophoretictechnique or the like. The electrophoretic technique is a preferredcoating technique and may be accomplished, for example, in a solution ofacetic acid, acetone, water and collagen with a metal stent as thecathode, at a potential of about three volts. This process bears someresemblance to modern electroplating, where positively charged metalions are reduced to their corresponding metal at the negatively chargedcathode. In the case of collagen, the biomolecule is dissolved orsuspended in an acidic solution. The acid imparts a positive charge tothe protein, collagen, and allows it to travel in an electrical field.By attaching a metal object to the negative electrode of a power source,and then immersing both the positive and negative electrodes in theacidic collagen solution, a layer of collagen will form on thenegatively charged surface. The result is a coated stent of the typeshown in FIGS. 19 and 20 which will preferably include openings in thecoating coincident with the openings in the stent.

EXAMPLE Collagen Coated Stent (Type IV) via Electrodeposition

A. A solution of Sigma type IV human collagen (50 mg) was placed in apolypropylene tube with 3 ml water, 1 ml of acetic acid and 2 ml ofacetone. This mixture was homogenized to a viscous solution via highshear mixing for ca. 3 minutes. The solution was diluted with water,then filtered through a cotton plug. The solution was allowed to standfor 1 hour to eliminate air bubbles.

B. A cylindrical container was fashioned out of polypropylene andcharged with 1 ml of the above prepared solution A. To this containerwas added a nitinol substrate attached to the negative lead of avariable voltage power supply which was set at 3 volts. The positiveelectrode was furnished with a 0.010 inch diameter wire which was placedca. 4 mm from the substrate. The power supply was turned on and gasevolution was immediately evident on the surfaces of each electrode.This was maintained for several minutes, then the electrodes wereremoved from the collagen solution. An even gelatinous mass was evidenton the substrate, which contained several bubbles. Upon standing for 1to 2 minutes, the bubbles were gone, and the electrodes were once againplaced in the bath. After three additional minutes of treatment, thesubstrate was withdrawn from the bath and allowed to dry. The coatingappeared to be continuous via visual inspection.

Another coating technique is shown in U.S. Pat. No. 5,275,826 which isincorporated herein by reference.

Referring now to FIG. 9, a tubular metal stent generally indicated at 10carries within it a cylindrical liner or inner sleeve of collagenmaterial generally indicated at 12 to provide a combination stent/linergenerally indicated at 14 for the purpose of vascular implantation.

Stent 10, as already described hereinabove, is of any type, typically ametal such as for example stainless steel, nitinol, superelastic alloysand other metals or a suitable polymer or any other suitable materialand may be of a fixed diameter or of a variable diameter, the latterbeing more preferred and well known in the art. The content of thisapplication is incorporated herein by reference.

Collagen liner 12 as described hereinbefore, may be of collagen per seor it may be applied directly to the stent or it may be carried as 12 con a support 12 d as shown in FIG. 10 for application to a stent.

When the collagen liner is comprised of two different materials whichare joined together as shown in FIG. 10, it may be referred to as abilayer structure. When placed in a stent, layer 12 c is placedluminally with layer 12 d contacting the inner surface of the stent.Layer 12 d, which may be in contact with the vessel wall throughopenings in the stent in such an arrangement, is preferably strong andenables the inner luminal layer 12 c itself to have the structuralintegrity necessary to ensure ease of loading, delivery and deployment.Layer 12 c may for example be comprised of a collagenous material in therange of 5 to 200 microns thick. Such a biologically derived materialmay be harvested from a donor source, cleaned of unwanted tissues andformed into the tube by wrapping it around a mandrel and bonding thematerial to itself. Synthetic materials may be used to comprise thesupport of layer 12 d of the liner, however, vascular graft materialssuch as PTFE, woven dacron, polyurethane and the like may also be used.Resorbable polymers (PLLA, PGA, PDLLA, PHB, polyanhydrides) are anotherchoice for the support layer 12 d of the liner 12. These materials maybe formed into a tube by extrusion, solvent casting, injection molding,etc. or spinning into fibers and weaving into a tubular structure. Atube of one of the aforementioned polymers may also be constructed by anon-woven fiber technique.

The innermost or luminal side, i.e., layer 12 c of the liner serves adifferent function than the support layer 12 d. The luminal surface orlayer 12 c must be a substrate for the growth of endothelial cells, aswell as a reservoir for therapeutic agents. Preferred material isfibular Type I collagen and/or porcine Type IV collagen in the range of5-200 microns thick, although fibrin may also be used for this purpose.Highly hydrated materials, such as cross linked hydrogels meet the drugholding requirement for the luminal portion of the liner, examples ofwhich are polyethers, polyalcohols, polypyrollidones, polypeptides,polyacids and the like. The layer 12 may also be a mixture of the abovematerials with a drug binding, ionic or covalent, molecule. One suchmolecule would be protamine, which effectively ionically binds heparin.These polymers can also be treated with growth factors, such as RGDpeptides to promote endothelialization. The preferred method of drugincorporation would involve the preparation of a solution of thetherapeutic agent and allowing the dehydrated luminal side of the sleeveto swell with the solution. Upon evaporation of he carrier solvent, thedrug would be made to reside in the matrix which comprises the innerlayer of the liner, i.e., layer 12 c. The device may act as a sponge tosoak-up a drug in solution and to elute it from the stent uponimplantation.

The term “collagen” or “collagen material” should also be understood toinclude the material referred to as Small Intestine Submucosa (SIS)which has particular use in this invention, alone and in combinationwith other collagen material such as Type I. SIS is comprised of abilayer structure in which one layer is predominantly (stratumcompactum) Type IV and the second layer is a mixture of Type I(muscularis mucosa) and Type III material. It is described in detail inU.S. Pat. Nos. 4,902,508; 4,956,178 and 5,281,422, all of which areincorporated herein by reference. The luminal side of the SIS as used inpreferred embodiments of this invention are predominantly a Type IVcollagen material.

As with other collagen material, SIS may be used herein with or withouta support layer such as a layer 12 d as shown in FIG. 10. It may also beused as the support layer 12 c in combination with a layer 12 d of TypeI collagen as shown in FIG. 10. SIS functions well without a supportlayer because it is itself a multi-layer structure.

In yet another embodiment, an SIS layer may be combined with a Type Ilayer to provide a one-way flow structure with reservoir arrangement asshown schematically in FIG. 11. In this arrangement, a cylindrical wiremesh stent 10 carries a tubular bilayer liner generally indicated at 12comprised of two layers 12 c and 12 d. Layer 12 c contacts the innersurface of stent 10 and is a Type I collagen material and may carry adrug or the like, acting as a reservoir. Luminal layer 12 d is SISmaterial and inherently functions to allow flow of drug from layer 12 cinto the luminal interior of the stent through the luminal layer 12 d ofstent 10 but does not permit appreciable fluid flow into layer 12 c fromthe interior of the stent.

Variations of this FIG. 11 arrangement are shown in FIGS. 12 and 13. InFIG. 12, stent 10 carries an inner or luminal liner made up of layers 12c and 12 d as described for FIG. 11 and an outer layer of the samecombination to allow predominantly one-way flow of drug to the luminalinterior of the stent and to the surface against which the stent restswhen implanted.

In FIG. 13, stent 10 carries an exterior layer 12 of unsupported SISmaterial and an inner liner comprised of layers 12 c and 12 d as inFIGS. 11 and 12. Layer 12 c is Type I material acting as a drugreservoir as previously shown in Figures 11 and 12. Layer 12 d is of SISacting as the one-way flow-through for drugs and the like from layer 12c, as before.

As pointed out hereinabove, cells of the blood vessel wall synthesizeand secrete several kinds of macromolecules forming extracellularmatrix. Each of these macromolecules may be combined in a multitude ofcombinations to form composites. Such materials as already pointed out,are referred to herein generally as “collagen”.

A primary result of the use of a collagen liner made of naturalcomponents is that cellular regrowth of endothelium will take place ontoa natural surface that is essentially undamaged and uniform. In thisregard, the liner provides biological protection.

The liner may be tightly fitted to the stent in much the same way asdescribed hereinabove with reference to the outer sleeve arrangement.

The liner may be attached to the stent in a wide variety of ways. Thebasic goal of attachment in the preferred form is to provide a stentdevice in which the supporting stent framework is substantially, if notcompletely, isolated from the blood flow by the liner. This can beachieved by placing liner 12 in the inside dimension of the stent 10 andcuffing the ends of the liner over the ends of the stent as shown at 16in FIG. 14. This is an especially preferred arrangement. Cuffs 16 mayeither be under or over the outer sleeve. Cuffs 16 may be sutured to thestent, sutured from one cuff to the other, or otherwise bonded to thestent or to the liner itself. The collagen material may be welded, bythe application of localized heat and pressure, or the application of aconcentrated solution of collagen material which acts like glue.

The liner may also be attached to the stent by the use of pledgets (notshown). The pledget (or small swatch of material) can be placed on theoutside of the stent. The liner, which resides on the luminal or innersurface of the stent, may be bonded to the pledget in a variety of ways.Among these are suturing, gluing and heat welding. In the case of acombination of liner with outer sleeve, these means of attachment may beused as well.

The liner may be placed in the stent via several methods. The stent maybe made porous or perforated, thus allowing the liner material to act asa forming mandrel for a collagen sleeve. The collagen may also beprecipitated onto the stent. This method would require the stent to beheated in a solution of collagen. The collagen forms a matrix on thesurface of the stent, then when properly annealed, the collagen assumesa fibular, well organized structure conducive for the attachment andgrowth of cells.

A technique is indicated in FIG. 15 in which the collagen 12 is castinside the stent 10 in a manner similar to that described in connectionwith FIG. 8. Upon set-up, the stent with a liner of cast collagen isremoved from the mold and a hole may be formed through the collagen toprovide a longitudinal opening therethrough. Otherwise, a mandrel ormold insert (not shown) may be used for this purpose also. Holes mayalso be formed through the stent walls in the collagen if the stent isperforated or the like.

The liner may be attached to the stent by any of several design featureswhich may be incorporated into the stent. By providing the stent withhooks, or other similar topography (not shown), the sleeve may bereadily attached to the stent. The sleeve material may be impaled onsuch barbs, thus securing the sleeve. With hooks of the appropriatesize, the collagen material may not be perforated, but rather embeddedin the holding topography.

As can be seen from the foregoing, the invention provides in oneembodiment a stent in which collagen liner material is placed withinand/or on the outside of the stent thereby reducing thrombus formationand therapeutically treating the vessel when a suitable agent isincluded in the collagen.

It is to be understood that the collagen material referred to herein aslayers may be in the form of sheets associated with the stent ordeposited thereon, i.e., as a coating.

Thus, the collagen material may be coated onto the stent surfaces asdesired by spraying or dip coating or electrodeposition or the like orattached in other ways as described above. Such a coating might be about1-50 microns thick. A coated stent is shown in FIG. 19, which willpreferably be perforate as shown.

A collagen coated stent may also have a collagen sleeve over thecollagen coating or under the collagen coating. For example, one mayplace a stent into a collagen sleeve, as shown in FIG. 1, with aninterference fit. The inside of the stent may then be coated withcollagen so that the stent and interior of the sleeve are covered andbonded together. Preferably, in such an arrangement, the sleeve will beSIS and the coating Type I or Type IV. It is also possible in the caseof an open-work stent such as shown in FIG. 1 or 3, to coat the stentstruts with collagen, place a collagen sleeve either over or inside thestent, or both, and then heat bond the sleeve and/or liner to thecoating. This would preferably be done with Type IV collagen, especiallySIS or with fibrin.

In some applications it may be desirable to include perforations in thecollagen for fluid movement through the stentcollagen wall. Such anarrangement is readily obtained as stents are generally open orperforate with respect to their structure and perforations may bereadily formed in a collagen liner, the perforations extending throughthe stent openings. Perforation in collagen liners of about 10-60microns in diameter have been found satisfactory. The distribution ofthe perforations may be such as to be evenly spaced, such as at 30-60micron spacing and to occupy about one-half of the liner surface areas.This, of course, may vary.

Lastly, there is a preferred orientation for placing collagen on thestent when the collagen is used in the form of a sheet which is wrappedaround the stent or a tube inserted in the stent. It has been discoveredthat sheet collagen has the ability to stretch but that itsstretchability is predominantly unidirectional. That is, most of thestretch is exhibited in one primary direction in a sheet. This is shownschematically by the parallel arrows 100 in FIG. 16 for a sheet ofcollagen 110 which typically shows little or no stretch in a directionnormal to the arrows.

It has been discovered that the collagen sheet, when used as a sleeve orliner on a stent which undergoes expansion and/or contraction, can bebetter accommodated if the collagen sheet is associated with the stenton a “bias”. This will be more fully explained by reference to FIGS. 17and 18. If a piece of collagen sheet 110 a is taken from sheet 110 inthe orientations shown in FIG. 17, it can be seen that the stretchdirection indicated by the arrows 100 is on a bias with respect to sheet110 a. In this case, the bias is 45° relative to the edges of sheet 110a. If sheet 110 a is oriented normally with respect to a stent 120 asshown in FIG. 18, i.e., the edges of sheet 110 a are normal to thelongitudinal dimension of stent 120, when sheet 110 a is wrapped aroundstent 120 to form a sleeve or rolled up (in direction shown at 112 inFIG. 18) into a tube for insertion into stent 120 as a liner, thestretch properties of sheet 110 a will be on a bias with respect to thelongitudinal dimension of stent 120, in this case the bias is 45°, whichis a preferred bias. Other degrees of bias are acceptable but 45° ispreferred.

It can be seen from the foregoing that due to the variable dimensions inboth diameter and length which occurs with stents, such an arrangementbetter accommodates collagen sleeves and liners to dimensional changesin both directions without disruption at seams and without tears in thematerial.

One preferred type of stent for use in this invention is one of the typedisclosed in related application 08/246,320, filed May 19, 1994, theentire content of which is incorporated herein by reference.

FIGS. 19 and 20 show a coated stent generally indicated at 140, thecollagen coating 142 being best seen in FIG. 20. Coating 142 is shown onboth the inside and outside surfaces of the stent although it may be oneither as well.

It can be seen from the above that the invention also provides atreatment method of implanting a stent in which collagen material isplaced between the stent and the vessel wall thereby reducing thrombusformation and therapeutically treating the vessel when a suitable agentis included in the collagen.

The above Examples and disclosure are intended to be illustrative andnot exhaustive. These examples and description will suggest manyvariations and alternatives to one of ordinary skill in this art. Allthese alternatives and variations are intended to be included within thescope of the attached claims. Those familiar with the art may recognizeother equivalents to the specific embodiments described herein whichequivalents are also intended to be encompassed by the claims attachedhereto.

What is claimed is as follows:
 1. A method of applying a collagencoating on a stent having a metal surface, comprising the steps of:immersing the stent in an aqueous electrolyte solution includingcollagen, an electrical potential being established between the anodeand cathode adequate to sustain electrodeposition of the collagen fromthe solution onto the metal surface of the stent coating the metalsurface with collagen by electrodeposition, the stent functioning as acathode in an anode/cathode pair; and placing a tubular material aboutthe stent or within the stent.
 2. The method of claim 1 wherein thetubular material comprises collagen.
 3. The method of claim 2 whereinduring the placing step, the tubular material is placed about the stent.4. The method of claim 2 wherein during the placing step, the tubularmaterial is placed within the stent.
 5. The method of claim 1 whereinthe stent is a self-expanding stent.
 6. The method of claim 1 whereinthe stent is a balloon-expandable stent.
 7. The method of claim 2wherein the tubular material includes a therapeutic agent.
 8. The methodof claim 7 wherein the therapeutic agent comprises heparin.
 9. Themethod of claim 2 wherein the tubular material is perforated.
 10. Themethod of claim 9 wherein the perforations are about 10-60 microns indiameter.
 11. The method of claim 1 wherein the tubular materialcomprises at least two types of collagen.
 12. The method of claim 11wherein the tubular material is in the form of a bilayer.
 13. The methodof claim 11 wherein the tubular material includes Type I and Type IVlayers.
 14. A method of applying a collagen coating on an expandablestent, wherein the expandable stent has as metal surface, comprising thesteps of: coating the metal surface with collagen by electrodeposition,wherein the expandable stent is expandable from a collapsed deliverydiameter to an expanded deployment diameter, such that the deliverydiameter is reduced from the deployment diameter, wherein the stentfunctions as a cathode in an anode/cathode pair and is immersed in anaqueous electrolyte solution including collagen and an electricalpotential is established between the anode and cathode adequate tosustain electrodeposition of the collagen from the solution onto themetal surface of the stent, wherein the stent is inflation expandablefrom a collapsed delivery diameter to an expanded deployment diameter,such that the delivery diameter is reduced from the deployment diameter,and covering the stent with a sleeve of collagen material.